Katherine Hasal, MS

SAN DIEGO — The oral disease-modifying drug under development for the treatment of relapsing-remitting multiple sclerosis (RRMS), teriflunomide, was not superior to interferon beta-1a (IFNbeta-1a) in risk of treatment failure, according to research presented at the Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Teriflunomide, the active metabolite of leflunomide, has been used in the treatment of rheumatoid arthritis since 1998. It works by blocking the proliferation and functioning of activated T and B lymphocytes by selecting inhibiting the critical mitochondrial enzyme, dihydro-orotate dehydrogenase (DHODH), which affects pyrimidine biosynthesis in quickly dividing lymphocytes but leaves the immune system’s response to infection uncompromised.

Patrick Vermersch, MD, of the University of Lille Norde de France in Lille, France, and colleagues conducted the 2-year, phase III TENERE study, a multicenter, randomized, parallel-group, rater-blinded study comparing the effectiveness and safety of teriflunomide 7 mg or 14 mg and subcutaneous IFNbeta-1a three times per week in 324 patients with RRMS. The primary endpoint was time to failure, which was defined as the first occurrence of confirmed relapse or permanent treatment discontinuation for any reason, whichever came first.

Overall, 48.6, 37.8, and 42.3% of patients failed treatment with teriflunomide 7 mg, 14 mg, and IFNbeta-1a, respectively. However, the rate of permanent treatment discontinuation was lower with teriflunomide (18.3 and 19.8%) than in the IFNbeta-1a group (28.8%).

The secondary endpoint, of annualized relapse rate (ARR) was not statistically significantly different for teriflunomide 14 mg compared with IFNbeta-1a (0.259 vs. 0.216, respectively), but teriflunomide 7 mg ARR was higher (0.410). At Week 48, treatment satisfaction was higher for both teriflunomide doses compared with IFNbeta-1a.

Both teriflunomide doses were well tolerated with no new or unexpected safety signals detected. Teriflunomide treatment was most commonly associated with nasopharyngitis, diarrhea, hair thinning, and back pain. IFNbeta-1a treatment was most commonly associated with alanine aminotransferase levels, headache, and flu-like symptoms. The rate of permanent treatment discontinuation in the study due to a treatment-emergent adverse event was higher in the IFNbeta-1a group compared with either teriflunomide dose (21.8 vs. 8.2 vs. 10.9%, respectively).

“No statistical superiority was observed when comparing the two teriflunomide groups and IFN-beta-1a on risk of failure, the primary composite endpoint. The rate of permanent treatment discontinuation was lower in both teriflunomide groups than in the IFN-beta-1a group. Both doses of teriflunomide were well tolerated,” the authors concluded.

This research was supported by Genzyme, a sanofi company.

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The oral disease-modifying drug under development for the treatment of relapsing-remitting multiple sclerosis, teriflunomide, was not superior to interferon beta-1a in risk of treatment failure.

CMSC 2012: Oral Teriflunomide Not Superior to Interferon in Risk of Treatment Failure

SAN DIEGO — In the course of a 24-week cessation of treatment with the humanized monoclonal antibody, natalizumab, in patients with relapsing-remitting multiple sclerosis (RRMS), pharmacokinetic, pharmacodynamic, and serum immune parameters normalized by 4 months, according to research presented at the Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Natalizumab treatment duration has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare but often lethal and untreatable disorder of the central nervous system characterized by large white-matter lesions that occur in immunocompromised patients. The RESTORE study was designed to investigate the effects of natalizumab interruption on MS disease activity.

Natalizumab works by directly binding to the alpha 4-integrin submit of very late activation antigen-4 (VLA-4), which reduces the availability of unblocked alpha-4, leading to an inhibition of immune cell extravasation across the blood-brain barrier.

Hans-Peter Hartung, MD, of the Heinrich-Heine University in Düsseldorf, Germany, and colleagues conducted the randomized, partially placebo-controlled exploratory RESTORE study. The objective was to evaluate the effects of a 24-week treatment interruption on MS disease activity in 175 patients who had been relapse-free after treatment with natalizumab for a year or more and had no gadolinium-enhancing (Gd+) lesions on baseline MRI scan.

Patients received either natalizumab, placebo, or in an open-label fashion, an alternative immunomodulatory therapy, such as interferon beta-1a (IFNbeta-1a), glatiramer acetate, or methylprednisolone. Rescue treatment with natalizumab or high-dose corticosteroids was allowed if patients experienced a clinical relapse, 1 new Gd+ lesion over 0.8 cubic centimeters in volume, or 2 or more gadolinium lesions.

After 4 months of natalizumab treatment interruption, serum concentrations of natalizumab and soluble vascular cell adhesion molecule (sVCAM), alpha-4 integrin receptor saturation, CD49d (alpha-4 integrin) expression, and circulating lymphocyte subsets, including CD34 hematopoietic cells, were consistent with results obtained from patients who had never been treated with natalizumab. It is important to note, however, that as these pharmacokinetic, pharmacodynamic, and immune parameters normalized, MRI and disease activity returned.

“Within 4 months of natalizumab treatment interruption, pharmacokinetic, pharmacodynamic, and immune parameters returned to baseline levels similar to those in non-natalizumab-treated patients,” the authors concluded.

This research was supported by Biogen Idec Inc. and Elan Pharmaceuticals, Inc.

In the course of a 24-week cessation of treatment with the humanized monoclonal antibody, natalizumab, in patients with RRMS, pharmacokinetic, pharmacodynamic, and serum immune parameters normalized by 4 months.

CMSC 2012: Immune Parameters Normalize Within 4 Months of Natalizumab Cessation in the Treatment of RRMS

SAN DIEGO — People discharged from the hospital with multiple sclerosis (MS) are 30% less likely to have had a myocardial infarction (MI) and 58% less likely to have ischemic heart disease (IHD), according to research presented at the Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Although it is known that perivascular inflammation is an early event in the process of plaque formation in MS, the information on vascular risk factors in MS is limited. Patient age may play a role in the prevalence of vascular disease in this population.

Nabeel Herial, MD, of the University of Toronto Medical Center in Toledo, OH, and colleagues conducted a study using data from the 2006 Nationwide Inpatient Sample (NIS) to evaluate the prevalence of IHD, MI, ischemic stroke (IS), and hemorrhagic stroke (HS) in 6,611,263 hospital discharges involving cases who had a secondary MS discharge diagnosis of MS and control patients who had no MS diagnosis from more than 1,000 hospitals in 38 states.

Of the total discharges, 0.32% (20.843) had a secondary diagnosis of MS. Average MS case patient age was 57.3 years, 73% were female, and 81% were Caucasian. Control patients were 60% female and 69% Caucasian.

Ischemic stroke (1.5 vs. 1.9%) and hemorrhagic stroke (0.3 vs. 0.37%) did not differ between MS and control patients. However, the rate of ischemic heart disease (1.6 vs 3.7%) and myocardial infarction (1.3 vs 2.1%) were lower for MS patients than for those with no MS. Overall, MS patients were 30% less likely to have MI and 58% less likely to have IHD.

“IHD and MI occur less frequently in MS discharges compared to controls. This analysis represents a large, uniform sample across the United States hospital discharges for the year 2006. Similar results were found when data for 2007 were queried,” the authors concluded.

People discharged from the hospital with MS are 30% less likely to have had a myocardial infarction and 58% less likely to have ischemic heart disease.

CMSC 2012: Ischemic Heart Disease and Myocardial Infarction Occur Less Frequently in Hospital Discharges with Multiple Sclerosis

	SAN DIEGO — Treatment with the investigational oral treatment for relapsing-remitting multiple sclerosis (RRMS), dimethyl fumarate (also known as BG-12), yielded significant reductions in the annualized relapse rate (ARR) and risk of relapse, according to research presented at the Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and America’s Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

	Dimethyl fumarate, currently under review by US and European regulators as a monotherapy treatment for RRMS, is thought to have both anti-inflammatory and neuroprotective effects. Its efficacy has been studied in two phase 3 trials—the DEFINE and CONFIRM studies.

	Robert J. Fox, MD, of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic in Ohio, and colleagues reported results from the multicenter, randomized placebo-controlled phase III CONFIRM study involving 1,417 patients aged 18 to 55 years with RRMS and an Expanded Disability Status Scale (EDSS) score less than 5 who received either placebo, dimethyl fumarate 240 mg twice daily (BID), or 240 mg three times per day (TID). An active comparator arm was also included, in which patients received subcutaneous glatiramer acetate, 20 mg/day.

	At 2 years, ARR was statistically significantly reduced by 44 percent, 51 percent, and 29 percent for dimethyl fumarate BID, TID, and glatiramer acetate, respectively, compared with placebo.

	Similarly, risk of relapse was also statistically significantly reduced by 34 percent, 45 percent, and 29 percent for dimethyl fumarate BID, TID, and glatiramer acetate, respectively, compared with placebo.

	The 12-week confirmed disability progression was also reduced by 21 percent, 24 percent and 7percent for dimethyl fumarate BID, TID, and glatiramer acetate, respectively, compared with placebo.

	The adverse event profile and incidence of serious adverse events was similar across all treatment groups. The most common adverse events associated with dimethyl fumarate were flushing or reddening of the skin, nausea, and diarrhea, especially during the first month of treatment but much less frequently thereafter. The incidence of serious infections were low and similar between groups, and no malignancies were reported.

	"Clinical efficacy results from CONFIRM are consistent with and further support those from DEFINE and suggest that BG-12 has the potential to be a valuable treatment option for patients with RRMS," the authors concluded.

	This research was supported by Biogen Idec Inc.

Treatment with the investigational oral treatment for relapsing-remitting multiple sclerosis, dimethyl fumarate (aka BG-12), yielded significant reductions in the annualized relapse rate and risk of relapse.

Katherine Hasal, MS

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